The ?-thalassemias and sickle cell disease are serious genetic blood diseases, which are WHO- designated as a growing global health burden. The disorders decrease production or alter structure of the b-chain of adult hemoglobin A and are characterized by anemia, chronic organ damage, and early mortality. HbF is another type of normal hemoglobin which is suppressed in infancy. Decades of research have shown that any incremental increase in HbF reduces the severity of sickle cell disease and the life-threatening anemia of b-thalassemia. Pharmacologic augmentation of fetal hemoglobin (g-globin chain) production, to replace the defective or missing b-globin chains, is accepted as a therapeutic modality. Only one therapeutic, hydroxyurea, is approved for sickle cell disease, and no definitive therapeutic agent is approved for beta thalassemia. Additional HbF- inducing therapies are needed. We utilized a novel high-throughput screening program to interrogate a library of drugs which are already EMEA or FDA-approved for other medical conditions, and identified a panel of previously unrecognized potent HbF-inducing drugs. HbF-inducing activity was validated in a secondary reporter assays, in patients' erythroid progenitors, and 3 lead therapeutics were evaluated in baboons on our Phase I STTR grant. This primate model has been predictive of subsequent human responses for other drugs. One therapeutic, Benserazide, was particularly intriguing in inducing high-level fetal globin, by 33-fold over baseline, with brif treatment in the baboon. We found the drug suppresses two components of a major repressor complex of the fetal hemoglobin gene. The drug has been used for 3 decades in Europe and Canada as a PK enhancer of levodopa for treatment of Parkinson's disease, and has a benign safety profile. Accordingly, we propose to repurpose Benserazide for treatment the beta hemoglobinopathies. Our Aims include: Aim I: Determine an optimal dosing regimen of Benserazide for inducing sustained HbF in vivo in anemic nonhuman primates Aim II: Produce a formulation suitable for a dose-ranging trial in hemoglobinopathy patients Aim III: Obtain a US IND to evaluate the EU-approved therapeutic in patients with sickle cell disease and beta thalassemia